Method for synthesizing 3-spiro three-membered ring indolinone derivative

Abstract

The present invention provides a method for synthesizing a 3-spiro three-membered ring indolinone derivative, which comprises under a protective atmosphere, reacting a 3-indol-ethanol compound as a reaction raw material at 20-60° C. in the presence of an additive and an organic base in an organic solvent, to obtain a 3-spiro three-membered ring indolinone compound after the reaction is complete. The additive is N-bromosuccinimide (NBS) or N-chlorosuccinimide (NCS). The method of the present invention does not require a metal catalyst, and the 3-spiro three-membered ring indolinone derivative is synthesized in one step in the presence of NBS or NCS. The reaction conditions are mild, the operations are simple and safe, and the yield is high.

What is claimed is: 
     
       1. A method for synthesizing a 3-spiro three-membered ring indolinone derivative, comprising steps of:
 under a protective atmosphere, reacting a compound of formula (I) or formula (III) at 20-60° C. in the presence of an additive and an organic base in an organic solvent, to obtain a compound of formula (II) or formula (IV) after the reaction is complete, wherein the additive is N-bromosuccinimide (NBS) or N-chlorosuccinimide (NCS); and 
 the reaction routes are as follows, wherein the formula (I) is exclusive of the formula (III): 
 
       
         
           
           
               
               
           
         
         wherein in formulas (I)-(IV), R 1  is selected from hydrogen, C1-C4 alkyl or halo; R 2  is hydrogen, C1-C4 alkyl, benzyl or phenyl; Ar is selected from phenyl, substituted phenyl or thienyl, in which the substituent on the substituted phenyl is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy or any combination thereof; and X is chloro or bromo. 
       
     
     
       2. The method according to  claim 1 , wherein the organic base is selected from the group consisting of triethylenediamine, 1,8-diazabicycloundec-7-ene, sodium hydride, trimethylamine and any combination thereof. 
     
     
       3. The method according to  claim 1 , wherein the molar ratio of the compound of formula (I) or formula (III) to the additive is 1:1-3. 
     
     
       4. The method according to  claim 1 , wherein the organic solvent is selected from the group consisting of 1,2-dichloroethane, 1,2-dichloromethane, toluene, 1,4-dioxane, ethyl acetate, acetonitrile and any combination thereof. 
     
     
       5. The method according to  claim 1 , wherein R1 is selected from hydrogen, methyl or halo. 
     
     
       6. The method according to  claim 1 , wherein R2 is selected from hydrogen, methyl, benzyl or phenyl. 
     
     
       7. The method according to  claim 1 , wherein Ar is selected from phenyl, substituted phenyl or thienyl, in which the substituent on the substituted phenyl is selected from halo, methoxy or methyl. 
     
     
       8. The method according to  claim 1 , wherein the time of reaction is 6-15 h. 
     
     
       9. The method according to  claim 1 , wherein the protective atmosphere is selected from argon, oxygen, air and any combination thereof. 
     
     
       10. The method according to  claim 1 , wherein the halo is selected from fluoro, chloro or bromo.